Purine derivatives

ABSTRACT

The present invention provides antiviral compounds of Formula (I): ##STR1## pharmaceutical compositions prepared therefrom, and methods of treatment of viral infections therewith.

This is a Divisional of application Ser. No. 07/285,399 filed Dec. 6,1991 now abandoned which is a continuation-in-part of Ser. No. 777,188filed Sep. 18, 1985, now abandoned.

The present invention relates to compounds having antiviral activity,processes for their preparation and pharmaceutical compositionscontaining them.

The compound 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine of formula(A) ##STR2## is disclosed in Synthetic Communications, 2(6), 345-351(1972) but no pharmaceutical activity has been indicated for thecompound in this document. We have subsequently shown that the compoundof formula (A) does have pharmaceutical activity, and this is disclosedin our Published European Pat. Appn. 0141 927.

We have now prepared a series of analogues of the compound of formula(A) which has useful oral absorption properties and is converted in vivoto the compound of formula (A) which has anti-viral activity.

According to the present invention there is provided a compound offormula (I) ##STR3## or a salt thereof, wherein R₁ and R₂ are eachindependently hydrogen, acyl or phosphate, provided that when one of R₁or R₂ is phosphate, the other is hydrogen; or R₁ and R₂ are joinedtogether to form a cyclic acetal group, a cyclic carbonate group or acyclic phosphate group.

Examples of acyl groups for R₁ and R₂ are those where the group R₁ O--or R₂ O-- is a pharmaceutically acceptable ester group, such as acarboxylic ester group.

Suitable acyl groups for R₁ and R₂ are ##STR4## where R₃ is C₁₋₆ alkyl,C₁₋₆ alkoxy, or optionally substituted aryl.

As used herein the term `aryl` includes phenyl which may be optionallysubstituted with one or two groups selected from C₁₋₆ alkyl, C₁₋₆ alkoxyor halo such as fluoro or chloro.

Preferably R₃ is methyl, ethyl, propyl, methoxy, or phenyl.

Suitably when R₁ and R₂ are joined together, they constitute a group##STR5##

A suitable example of a compound of formula (I) is the compound whereone of R₁ or R₂ is ##STR6## and the other is hydrogen.

In the case of compounds of formula (I) wherein one of R₁ or R₂ is anacyl or phosphate group, the compound exists in two enantiomeric forms.The invention includes both enantiomers in isolated form and mixturesthereof.

The compounds of the invention may be in crystalline form or as hydratesand it is intended that both forms are encompassed by the expression`compound of formula (I)` used herein.

Salts of the compound of formula (I) are preferably pharmaceuticallyacceptable, but non-pharmaceutically acceptable salts are also withinthe scope of the present invention, since these are useful asintermediates in the preparation of pharmaceutically acceptablecompounds.

Examples of pharmaceutically acceptable salts of the compound of formula(I) are acid addition salts formed with a pharmaceutically acceptableacid such as hydrochloric acid, orthophosphoric acid and sulphuric acid.

When the compound of formula (I) contains a phosphate group suitablesalts include metal salts, such as aluminum, alkali metal salts such assodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy-lower alkylaminessuch as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine.

Suitable compounds of formula (I) include;

2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine;

2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine;

2-amino-9-(4-acetoxy-3-hydroxymethylbut-1-yl)purine;

2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine;

2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine;

2-amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine;

2-amino-9-(4-butyryloxy-3-hydroxymethylbut-1-yl)purine;

2-amino-9-(4-benzoyloxy-3-hydroxymethylbut-1-yl)purine;

2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine 4'-phosphate;

2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine 4':4"phosphate;

and pharmaceutically aceptable salts thereof.

The compounds of the present invention are potentially useful in thetreatment of infections caused by herpes viruses, such as herpes simplextype 1, herpes simplex type 2 and varicella zoster viruses.

Accordingly, the present invention also provides a compound of formula(I) or a pharmaceutically acceptable salt thereof, for use as an activetherapeutic substance and in particular for use in the treatment ofviral infections.

The compound of formula (I) wherein R₁ and R₂ are both hydrogen or asalt thereof may be prepared by hydrolysing the 1,3-dioxane ring of acompound of formula (II) ##STR7## and subsequently, if necessary,converting the compound of formula (I) thus formed to the free base orto a different salt thereof.

Preferably the hydrolysis of the compound of formula (II) is carried outin acid medium, conveniently aqueous hydrochloric acid.

The compound of formula (II) is itself an example of a compound offormula (I) and may be prepared by reducing a compound of formula (III)##STR8##

The reduction is preferably carried out catalytically, usingpalladium-on-charcoal, and the subsequent hydrolysis to the compound offormula (I) may be conveniently performed directly on the reactionproduct mixture.

The intermediate compound of formula (III) may be prepared by treating acompound of formula (IV) ##STR9## with a compound of formula (V)##STR10##

The reaction may be carried out in an inert organic solvent, preferablydimethylformamide, in the presence of an inorganic base, preferablypotassium carbonate.

The compound of formula (IV) may itself be prepared by brominating acompound of formula (VI) ##STR11##

The reaction is preferably carried out by treating the compound offormula (VI) with carbon tetrabromide and triphenylphosphine in anorganic, aprotic solvent such as dimethylformamide.

The compound of formula (VI) may itself be prepared by treating acompound of formula (VII) ##STR12## with 2,2-dimethoxypropane andp-toluenesulphonic acid in the presence of acetone or tetrahydrofuran.

Compounds of formula (I) werein R₁ and R₂ are acyl groups or are joinedtogether to form a cyclic carbonate group can be prepared by reductionof a compound of formula (VIII) ##STR13## wherein R₄ and R₅ are the sameor different acyl groups, or R₄ and R₅ are joined together to form acyclic carbonate group.

Suitable acyl groups for R₄ and R₅ include groups ##STR14## ashereinbefore defined.

The reduction is suitably carried out under conditions described abovefor the reduction of a compound of formula (III).

Compounds of formula (I) wherein R₁ and R₂ are acyl groups can beconverted to a compound of formula (I) wherein R₁ and or R₂ are hydrogenby conventional deacylation or partial deacylation processes. Forexample, reaction with methanolic ammonia can be used to effect completedeacylation to yield compound of formula (I) wherein both R₁ and R₂ arehydrogen. Reaction with a mild base such as potassium carbonate canresult in partial deacylation to produce a compound of formula (I)wherein one of R₁ or R₂ is hydrogen and the other is an acyl group.

Compounds of formula (VIII), may be prepared by treating the compound offormula (V) as hereinbefore defined, with a compound of formula (X)##STR15## in which R₄ and R₅ are as defined in formula (VIII) and Z is aleaving group such as Cl, Br or I, preferably Br.

The compound of formula (V) is a known compound.

Compounds of formula (X) in which Z is bromine may be prepared bybrominating a compound of formula (XI). ##STR16## preferably bytreatment with carbon tetrabromide and triphenylphosphine in an organic,aprotic solvent, such as dimethylformamide.

Compounds of formula (X) in which Z is Cl or I may be prepared in ananalogous manner.

Compounds of formula (XI) in which R₄ and R₅ are the same and are acylgroups may be prepared according to the following schematic process:##STR17## wherein R⁶ is a removable protecting group.

Suitably R₆ is a group removable by hydrolysis or hydrogenolysis.

Preferably R₆ is a group removable by hydrogenolysis such as benzyl.This group can be removed by conventional methods for example by usinghydrogen in the presence of a palladium/carbon catalyst.

Compounds of formula (XI) wherein R₄ and R₅ are joined together to forma cyclic carbonate group may be prepared by reaction of a compoundformula (XII)

    (HOCH.sub.2).sub.2 CH(CH.sub.2).sub.2 OR.sub.6             (XII)

wherein R₆ is a hereinbefore defined with phosgene or1,1'-carbonyldiimidazole, and thereafter if desired removing theprotecting group R₆. The reaction is suitably carried out in a dryorganic solvent such as pyridine at a temperature of from 0°-50° C.,conveniently at ambient temperature.

The above described processes for preparing the compound of formula(III) and compounds of formula (VIII) are also disclosed in PublishedEuropean European Patent Application No. 0141 927.

Compounds of formula (I) wherein R₁ and/or R₂ is acyl may be prepared byesterifying a compound of formula (I) wherein R₁ and R₂ is hydrogen byconventional methods. If necessary during the esterification process the--NH₂ group and optionally also one of the --OR₁, or --OR₂ groups may beprotected by a suitable protecting group such as trityl ormonomethoxytrityl. The product is subsequently deprotected for exampleby treatment with acid such as acetic acid. For example, compounds offormula (I) wherein R₁ O-- and/or R₂ O-- is a carboxylic ester group maybe prepared by reaction of a compound of formula (I) which has beenoptionally protected as described above with (a), an appropriatecarboxylic acid chloride or (b) an appropriate carboxylic acid anhydrideor (c) an appropriate carboxylic acid in the presence of a dehydratingagent such as dicyclohexylcarbodiimide (DCCI).

Compounds of formula (I) wherein R₁ and R₂ form a cyclic carbonate groupcan be prepared by reaction of a compound of formula (I) wherein R₁ andR₂ are hydrogen and the NH₂ group is optionally protected; with phosgeneor 1,1-carbonyldiimidazole, and thereafter if necessary deprotecting theproduct. Suitable protecting groups for the NH₂ group include trityl andmonomethoxytrityl as described above. The reaction is suitably carriedout in a dry organic solvent such as pyridine at a temperature of from0°-50° C., conveniently at ambient temperature.

Compounds of formula (I) wherein one of R₁ or R₂ is phosphate or R₁ andR₂ together form a cyclic phosphate can be prepared by treating acompound formula (XIII) ##STR18## wherein R₇ is a protecting group andR₈ and R₉ are hydrogen or a protecting group provided that one of R₈ orR₉ is hydrogen; with a phosphorylating agent and thereafter if desireddeprotecting resultant product. When R₈ and R₉ are both hydrogen, acyclic phosphate compound is produced. Suitable protecting groups for R₇and R₈ or R₉ are trityl or monomethoxytrityl. Deprotection of theresultant product can then be effected by treatment with acid such asacetic acid.

A suitable phosphorylating agent is phosphorus oxychloride, optionallyin the presence of a base such as pyridine.

In addition, when one of R₈ or R₉ is a protecting group cyanoethylphosphoric acid can be employed as a phosphorylating agent in order toproduce a compound of formula (I) wherein one of R₁ or R₂ is phosphate.

The reaction product after treatment with cyanoethyl phosphoric acid istreated with aqueous ammonia, which yields the ammonium salt of thephosphate ester as the final product.

Compounds of formula (XIII) can be prepared by protection of a compoundof formula (I) wherein R₁ and R₂ is hydrogen, for example by reactionwith a trityl or monomethoxytrityl halide such as monomethoxytritylchloride.

Alternatively compounds of formula (I) wherein R₁ and R₂ are joinedtogether to form a cyclic phosphate can be prepared from a compound offormula (I) wherein one of R₁ or R₂ is phosphate and the other ishydrogen by cyclisation of the monophosphate for example usingdicyclohexylcarbodiimide.

Compounds of formula (I) wherein one of R₁ or R₂ is acyl and the otheris hydrogen or R₁ and R₂ together form a cyclic acetal can be preparedby reacting a compound of formula (I) wherein R₁ and R₂ are hydrogenwith a compound of formula (XIV)

    (R.sub.10).sub.m C(OR.sub.11).sub.n                        (XIV)

wherein

R₁₀ is C₁₋₆ alkyl,

R₁₁ is C₁₋₆ alkyl,

m is 0,1 or 2, and

n is an integer of 2, 3 or 4

provided that m+n is equal to 4, and thereafter, if n is 3 or 4,hydrolysing the product.

When a compound of formula (I) in which R₁ and R₂ is a cyclic acetal isrequired, a compound of formula (XIV) wherein m is 2 and n is 2 isemployed. For example, when m is 2, n is 2 and R₁₀ is methyl, theproduct is the compound of formula (II) as hereinbefore defined. Thereaction is suitably carried out in an inert organic solvent such astetrahydrofuran or N,N-dimethylformamide, in the presence of an acidsuch as p-toluene sulphonic acid.

Where necessary the subsequent hydrolysis step is an aqueous hydrolysispreferably carried out in the presence of an acid such as p-toluenesulphonic acid.

Compounds of formula (XIV) are known compounds or can be prepared fromknown compounds by known methods.

Compounds of formula (I) or pharmaceutically acceptable salts thereofmay be formulated for use in a pharmaceutical composition. Accordingly,in a further aspect of the invention, there is provided a pharmaceuticalcomposition which comprises a compound of formula (I) orpharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or excipient.

A composition which may be administered by the oral route to humans maybe compounded in the form of a syrup, tablet or capsule. When thecomposition is in the form of a tablet, any pharmaceutical carriersuitable for formulating such solid compositions may be used, forexample magnesium stearate, starch, lactose, glucose, rice, flour andchalk. The composition may also be in the form of an ingestible capsule,for example of gelatin, to contain the compound, or in the form of asyrup, a solution or a suspension. Suitable liquid pharmaceuticalcarriers include ethyl alcohol, glycerine, saline and water to whichflavouring or colouring agents may be added to form syrups. Thecompounds may also be presented with a sterile liquid carrier forinjection.

The composition may also be formulated for topical application to theskin or eyes.

For topical application to the skin, the composition may be in the formof a cream, lotion or ointment. These formulations may be conventionalformulations well known in the art, for example, as described instandard books of pharmaceutics and cosmetics, such as Harry'sCosmeticology published by Leonard Hill Books and the BritishPharmacopaeia.

The composition for application to the eyes may be a conventionaleye-drop composition well known in the art, or an ointment composition.

Preferably, the composition of this invention is in unit dosage form orin some other form that the patient may administer to himself a singledose. A suitable dosage unit might contain from 30 mg to 1 g of activeingredient, for example 100 to 500 mg.

Such doses may be administered 1 to 4 times a day or more usually 2 or 3times a day. The effective dose of compound will in general be in therange of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0to 10 mg/kg per day.

No toxicological effects are indicated at the above described dosagelevels.

In a further aspect of the invention there is provided a method oftreating viral infections in a human or non-human animal, whichcomprises administering to the animal an effective, non-toxic amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

The following examples illustrate the invention.

EXAMPLE 1 2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine Method A

To a solution of2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.54g, 1.75 mmol) in ethanol (10 ml) and cyclohexene (20 ml) was added 10%palladium-on-charcoal (400 mg) and the solution was refluxed for 7hours. A further quantity of catalyst (200 mg) was added and thesolution was refluxed overnight. The solution was filtered and washedthrough with methanol. To the filtrate was added hydrochloric acid (5M,0.3 ml) and water (0.7 ml) and the solution was stirred for 30 minutesat room temperature. The solution was neutralised by addition of aqueoussodium bicarbonate and the solvent was removed. The residue was purifiedby column chromatography on silica gel eluting with chloroform-methanol(5:1, 4:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purineas a crystalline solid (150 mg, 36%), m.p. 156°-158° C.; λmax (H₂ O) 242and 303 nm; λmax (KBr) 3320, 3210, 1640, 1610, 1580, and 1430 cm⁻¹ ;δ_(H) [(CD₃)₂ SO] 1.47 (1H, m, 3'-H), 1.78 (2H, q, J 7.2 Hz, 2'-H),3.3-3.5 (4H, m, 2×4'-H), 4.12 (2H, t, J 7.4 Hz, 1'-H), 4.42 (2H, t, J5.2 Hz, D₂ O exchangeable, 2×OH), 6.45 (2H, s, D₂ O exchangeable,2-NH₂), 8.06 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 50.61; H,6.45; N, 29.62%. C₁₀ H₁₅ N₅ O₂ requires: C, 50.62; H, 6.37; N, 29.52%).

Method B (alternative reduction reaction)

To a solution of ammonium formate in methanol (400 mM, 3 ml) were added2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (90 mg,0.3 mmol) and 10% palladium-on-charcoal (28 mg) and the mixture washeated under reflux. After 1.5 hours reduction to2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine was complete.

EXAMPLE 2 9-(4-Acetoxy-3-acetomethylbut-1-yl)-2-aminopurine

A suspension of9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (0.36 g,1.0 mmol) and 10% palladium-on-charcoal (30 mg) in methanol containingammonium formate (400 mM, 10 ml) was heated under reflux for 30 minutes.The mixture was allowed to cool, filtered and the solvent removed. Theresidue was taken up in water and the solution extracted twice withchloroform. The organic layers were combined, dried (magnesium sulphate)and the solvent removed to afford9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (0.29 g, 90%).Recrystallisation from ethyl acetate-hexane gave white shiny plates(0.25 g, 78%) m.p. 102°-104° C.; λmax (MeOH) 222 (27,500), 244 (4,890),and 309 (7,160) nm; νmax (KBr) 3340, 3170, 1745, 1730, 1660, 1615 and1580 cm⁻¹ ; δ_(H) (CDCl₃) 1.90-2.05 (3H, m, 2'-H and 3' -H), 2.07 (6H,s, 2×CH₃), 4.15 (4H, d, J 5.2 Hz, 2×4'-H), 4.21 (2H, t, J 7.2 Hz, 1'-H),5.16 (2H, br s, 2-NH₂), 7.79 (1H, s, 8-H), and 8.70 (1H, s, 6-H);(Found: C, 52.10; H, 6.00; N, 21.49%. C₁₄ H₁₉ N₅ O₄ requires C, 52.33;H, 5.96; N, 21.79%).

EXAMPLE 3 2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine

To a suspension of9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (4.86 g,13.7 mmol) in methanol (140 ml) containing ammonium formate (400 mM) wasadded 10% palladium-on-charcoal (0.4 g) and the mixture was heated underreflux for 40 minutes. After cooling the solution was filtered and thesolvent removed. The residue was taken up in water and extracted withchloroform (100 ml and 50 ml). The organic layers were combined, dried(magnesium sulphate) and the solvent removed. The residue was dissolvedin methanol saturated with ammonia at 0° C. (150 ml) and the solutionwas stirred for 20 hours. The solvent was removed and the residuesuspended in chloroform (20 ml) and filtered. The solid wasrecrystallised from isopropanol-water and a second recrystallisation wascarried out from the mother liquors from ethanol (total 2.71 g, 83%).

EXAMPLE 4 9-(4-Acetoxy-3-hydroxymethylbut-1-yl)-2-aminopurine

To a solution of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine(0.48 g, 1.5 mmol) in methanol (9 ml) was added anhydrous potassiumcarbonate (14 mg, 0.1 mmol) and the solution was stirred for 20 minutes.Two drops of glacial acetic acid were added, the solution was filteredand the solvent was removed. The residue was purified by columnchromatography on silica gel eluting with chloroform-methanol (15:1,10:1) to afford 9-(4-acetoxy-3-hydroxymethylbut-1-yl)-2-aminopurine as awhite crystalline solid (124 mg, 30%), m.p. 166°-168°; ν_(max) (KBr)3440, 3220, 1720, 1650, 1615, and 1580 cm⁻¹ ; δ_(H) [(CD₃)₂ SO]1.68 (1H,m, 3'-H), 1.82 (2H, m, 2'-H), 1.98 (3H, s, CH₃), 3.41 (2H, t, J4.8 Hz,D₂ O exchange gives d, CH.sub. 2 OH), 3.9-4.05 (2H, AB part of ABX,J_(AB) 10.9 Hz and J_(AX) =J_(BX) 5.8 Hz, CH₂ OCO), 4.12 (2H, t, J 7.2Hz, 1'-H), 4.62 (1H, t, J 5.0 Hz, D₂ O exchangeable, OH), 6.44 (2H, s,D₂ O exchangeable, 2-NH₂), 8.07 (1H, s, 8-H), and 8.56 (1H, s, 6-H);(Observed M⁺, 279.1326. C₁₂ H₁₇ N₅ O₃ requires 279.1331).

EXAMPLE 5 2-Amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine

To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine(237 mg, 1.0 mmol) in dry tetrahydrofuran (3 ml) were addedp-toluenesulphonic acid monohydrate (0.21 g, 1.1 mmol) and tetramethylorthocarbonate (0.53 ml, 4.0 mmol) and the mixture was stirred for 100minutes. Water (0.8 ml) was added and after a further 15 minutes thesolution was neutralised by addition of aqueous sodium bicarbonate. Thesolvent was removed and the residue was extracted withchloroform-methanol (3:1). The solvent was removed and the residue waspurified by column chromatography on silica gel eluting withchloroform-methanol (10:1) to afford2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxbut-1-yl) purine which wasobtained as a white crystalline solid after trituration with ethylacetate (65 mg, 22%), m.p. 129°-132°; ν_(max) (KBr) 3440, 3220, 1745,1650, 1615, and 1580 cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 1.73 (1H, m, 3'-H), 1.81(2H, m, 2'-H), 3.41 (2H, t, 5.1 Hz, D₂ O exchange gives d, CH₂ OH) 3.68(3H, s, CH₃), 4.0-4.2 (4H, m, CH₂ OCO and 1'-H), 4.65 (1H, t, J 5.2 Hz,D₂ O exchangeable, OH), 6.44 (2H, s, D₂ O exchangeable, 2-NH₂), 8.06(1H, s, 8-H), and 8.55 (1H, s, 6-H); (Observed M⁺, 295.1286, C₁₂ H₁₇ N₅O₄ requires 295.1280).

EXAMPLE 6 2-Amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine

To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine(240 mg, 1.0 mmol) in N,N-dimethylformamide (3 ml) were addedp-toluenesulphonic acid monohydrate (210 mg, 1.1 mmol) and2,2-dimethoxypropane (0.62 ml, 5.0 mmol) and the solution was stirredfor 30 minutes. Potassium carbonate (110 mg, 0.8 mmol) was added and thesolution was stirred for a further 30 minutes. Water (10 ml) was addedand the solution was extracted with chloroform (3×8 ml). The organiclayers were combined, dried (magnesium sulphate) and the solventremoved. Trituration with toluene-ether afforded2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a whitecrystalline solid (262 mg, 94%) which was recrystallised from ethylacetate-hexane (216 mg, 78%), m.p. 118°-120°; λ_(max) (MeOH) 221(27,200), 244 (4,920), and 308 (7,130)nm; ν_(max) (KBr) 3450, 3140,1635, 1615, 1580, and 1435 cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 1.26 (3H, s, CH₃),1.33 (3H, s, CH₃), 1.58 (1H, m, 3'-H), 1.74 (2H, q, J 7.1 Hz, 2'-H),3.54 (2H, dd, J 11.8 Hz and 8.5 Hz, 2×H_(ax)), 3.78 (2H, dd, J 11.8 Hzand 4.4 Hz, 2×H_(eq)), 4.07 (2H, t, J 7.2 Hz, 1'-H), 6.46 (2H, s, D₂ Oexchangeable, 2-NH₂), 8.09 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found:C, 56.09; H, 6.91; N, 24.88%. C₁₃ H₁₉ N₅ O₂ requires C, 56.30; H, 6.91;N, 25.25%).

EXAMPLE 7 2-Amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine

A solution of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (0.21g, 0.9 mmol), 4-dimethylaminopyridine (10 mg) and propionic anhydride(0.64 ml, 5.0 mmol) in N,N-dimethylformamide (5 ml) was stirred for 16hours. The solvent was removed and the residue was partitioned betweenaqueous sodium bicarbonate and chloroform. The organic layer was dried(magnesium sulphate) and the solvent was removed. The residue waspurified by column chromatography on silica gel eluting withchloroform-methanol (20:1) to give2-amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine (160 mg,51%) which was recrystallised from ethyl acetate-hexane (115 mg, 37%),m.p. 77.5°-79°; λ_(max) (EtOH) 222 (27,300), 244 (5,020), and 309(7,110)nm; δ_(max) (KBr) 3390, 3210, 1735, 1650, 1605, 1580, 1525, 1475,and 1425 cm⁻¹ ; δ_(H) (CDCl₃) 1.14 (6H, t, J 7.6 Hz, 2×CH₃), 1.96 (3H,m, 2'-H and 3'-H), 2.34 (4H, q, J 7.6 Hz, 2×CH₂ CH₃), 4.15 (4H, d, J 5.5Hz, 2×CH₂ OOC), 4.21 (2H, t, J 7.0 Hz, 1'-H), 5.05 (2H, s, D₂ Oexchangeable, 2-NH₂), 7.77 (1H, s, 8-H), and 8.69 (1H, s, 6-H);(Observed M⁺ 349.1752. C₁₆ H₂₃ N₅ O₄ requires 349.1751).

9-(3-Hydroxymethyl-4-monomethoxytrityloxybut-1-yl)-2-monomethoxytritylaminopurine(Example 8) and9-(4-Hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine(Example 9)

To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine(2.37 g, 10 mmol) in N,N-dimethylformamide (40 ml) containing4-dimethylaminopyridine (30 mg) and triethylamine (4.2 ml) was added asolution of monomethoxytrityl chloride (6.8 g, 22 mmol) inN,N-dimethylformamide (60 ml) over a period of 40 minutes. The solutionwas stirred for a further 40 minutes, methanol (1 ml) was added and thesolvent was removed. The residue was taken up in chloroform and washedwith water and dilute aqueous sodium bicarbonate. The organic layer wasdried (magnesium sulphate) and the solvent was removed. The residue waspurified by column chromatography on silica gel eluting withchloroform-methanol mixtures (40:1 to 6:1).

The first product to elute was9-(3-hydroxymethyl-4-monomethoxytrityloxybut-1-yl)-2-monomethoxytritylaminopurinewhich was further purified by a second silica gel column eluting withchloroform-methanol (40:1) and obtained as a colourless foam (3.34 g,43%); λ_(max) (EtOH) 227 (47,400) and 312 (6,450)nm; ν_(max) (KBr) 3430,1615, 1580, 1510, 1490, and 1415 cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 1.37 (2H, m,2'-H), 1.49 (1H, m, 3'-H), 2.8-2.9 (2H, m, CH₂ OC), 3.2-3.4 (2H, m, CH₂OH), 3.64 (5H, m, 1'-H and OCH₃), 3.73 (3H, s, OCH₃), 4.40 (1H, t, J 5.0Hz, D₂ O exchangeable, OH), 6.7-7.4 (28H, m, Ar-H), 7.46 (1H, s, D.sub.2 O exchangeable, 2-NH), 7.88 (1H, s, 8-H), and 8.53 (1H, s, 6-H):(Found: C, 77.28; H, 6.27; N, 8.94%. C₅₀ H₄₇ N₅ O₄ requires C, 76.80; H,6.06; N, 8.96%

The second product to elute was9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurinewhich was obtained as a white crystalline solid after trituration andfiltration from ether (2.07 g, 41%), m.p. 181°-183°; ν_(max) (EtOH) 227(36,000) and 312 (6,780)nm; ν_(max) (KBr) 3390, 1615, 1580, 1525, 1510,1490, and 1420 cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 1.30 (1H, m, 3'-H), 1.39 (2H, q,J 6.8 Hz, 2'-H), 3.15-3.35 (4H, m, 2×4'-H), 3.70 (3H, s, OCH₃), 3.76(2H, t, J 7.2 Hz, 1'-H), 4.33 (2H, t, J 5.1 Hz, D₂ O exchangeable,2×OH), 6.8-7.4 (14H, m, Ar-H), 7.52 (1H, s, D₂ O exchangeable, 2-NH),7.97 (1H, s, 8-H), and 8.52 (1H, s, 6-H); (Found: C, 70.49; H, 6.24; N,13.41%. C₃₀ H₃₁ N₅ O₃ requires C, 70.71; H, 6.13; N, 13.74%).

EXAMPLE 10 2-Amino-9-(4-butyryloxy-3-hydroxymethylbut-1-yl)purine

To a solution of9-(3-hydroxymethyl-4-monomethoxytrityloxybut-1-yl)-2-monomethoxytritylaminopurine(0.70 g, 0.9 mmol) and 4-dimethylaminopyridine (10 mg) inN,N-dimethylformamide (5 ml) was added butyric anhydride (0.29 ml, 1.8mmol) and the solution was stirred for 15 minutes. Methanol (1 ml) wasadded and the solvent was removed. The residue was taken up in 80%acetic acid (9 ml) and the solution was stirred at 70° for 30 minutes.Water (2 ml) was added and the solution was extracted with hexane (2×10ml). The aqueous layer was retained and the solvent was removed. Theresidue was partitioned between saturated aqueous sodium bicarbonate andchloroform and the organic layer was dried (magnesium sulphate) and thesolvent removed. The residue was purified by column chromatography onsilica gel eluting with chloroform-methanol (16:1 to afford2-amino-9-(4-butyryloxy-3-hydroxymethylbut-1-yl)purine which wasobtained as a white crystalline solid after trituration with methanol(188 mg, 68%), m.p. 125°-127°; λ_(max) (MeOH) 222 (27,600), 243 (4,830),and 308 (6,950)nm; ν_(max) (KBr) 3190, 1730, 1640, 1620, and 1580 cm⁻¹ ;δ_(H) [(CD₃)₂ SO]0.85 (3H, t, J 7.4 Hz, CH₃), 1.50 (2H, sextet, J 7.3Hz, CH₂ CH₂ CH₃), 1.68 (1H, m, 3'-H), 1.82 (2H, m, 2'-H), 2.23 (2H, t, J7.4 Hz, CH₂ CH₂ CH₃), 3.42 (2H, t, J 5.2 Hz, D₂ O exchange gives d, CH₂OH), 3.95-4.1 (2H, ABX, J_(AB) 11.0 Hz, J_(AX) =J_(BX) 5.8 Hz, CH₂ OOC),4.12 (2H, t, J 7.3 Hz, 1'-H), 4.62 (1H, t, J 4.9 Hz, D₂ O exchangeable,OH), 6.44 (2H, s, D₂ O exchangeable, 2-NH₂), 8.06 (1H, s, 8-H), and 8.56(1H, s, 6-H); (Found: C, 54.41; H, 6.91; N, 22.70%. C₁₄ H₂₁ N₅ O₃requires C, 54.71; H, 6.89; N, 22.79%).

EXAMPLE 11 2-Amino-9-(4-benzoyloxy-3-hydroxymethylbut-1-yl)purine

To a solution of9-(3-hydroxymethyl-4-monomethoxytrityloxybut-1-yl)-2-monomethoxytritylaminopurine(0.70 g, 0.9 mmol) and 4-dimethylaminopyridine (10 mg) inN,N-dimethylformamide (5 ml) was added benzoic anhydride (0.61 g, 2.7mmol) and the solution was stirred for 1 hour. Methanol (1 ml) was addedand the solvent was removed. The residue was taken up in 80% acetic acid(9 ml) and the solution was stirred at 80° for 20 minutes. Water (3 ml)was added and the solution was extracted with hexane (2×10 ml). Theaqueous layer was retained and the solvent was removed. The residue waspartitioned between saturated aqueous sodium bicarbonate and chloroformand the organic layer was dried (magnesium sulphate) and the solventremoved. The residue was purified by column chromatography on silica geleluting with chloroform-methanol (14:1) to afford2-amino-9-(4-benzoyloxy-3-hydroxymethylbut-1-yl)purine which wasobtained as a white crystalline solid after trituration with methanol(235 mg, 76%), m.p. 116°-118°; λ_(max) (MeOH) 223 (36,700) and 309(6,680)nm; ν_(max) (KBr) 3320, 1710, 1610, and 1580 cm⁻¹ ; δ_(H) [(CD₃)₂SO]1.83 (1H, m, 3'-H), 1.93 (2H, q, J 7.1 Hz, 2'-H), 3.52 (2H, t, J 5.3Hz, D₂ O exchange gives d, CH₂ OH), 4.19 (2H, t, J 7.0 Hz, 1'-H),4.2-4.3 (2H, ABX, J_(AB) 11.0 Hz, J_(AX) =J_(BX) 5.6 Hz, CH₂ OOC), 4.69(1H, t, J 5.2 Hz, D₂ O exchangeable, OH), 6.43 (2H, s, D₂ Oexchangeable, 2-NH₂), 7.5-7.9 (5H, m, C₆ H₅), 8.10 (1H, s, 8-H), and8.55 (1H, s, 6-H); (Found: C, 59.20; H, 5.63; N, 20.82%. C₁₇ H₁₉ N₅ O₃requires C, 59.81; H, 5.61; N, 20.52%).

EXAMPLE 12 2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine4'-phosphate

To an ice-cooled solution of phosphorus oxychloride (0.10 ml, 1.1 mmol)in pyridine (2 ml) was added dropwise over 15 minutes a solution of9-(3-hydroxymethyl-4-monomethoxytrityloxybut-1-yl)-2-monomethoxytritylaminopurine(0.78 g, 1.0 mmol) in pyridine (2 ml). The solution was stirred for afurther 5 minutes at 0° and then for 30 minutes at room temperature. Thesolution was added dropwise to a solution of sodium bicarbonate (0.5 g,6.0 mmol) in water (7 ml). The solvent was removed and the residue wastaken up in 80% acetic acid (10 ml) and the solution was stirred at 70°for 25 minutes. The solvent was removed and the residue was taken up inwater and brought to pH 6 by addition of ammonia. The solution wasextracted twice with chloroform and the solvent was removed. The residuewas purified by preparative high pressure liquid chromatography on a C₁₈reverse-phase μ-Bondapack column eluting with 3% methanol in ammoniumacetate buffer (pH 4.5, 50 mM) to afford2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine 4'-phosphate as ahygroscopic white powder (85 mg, 25%); λ_(max) (H₂ O) 220, 241, and 303nm; ν_(max) (KBr) 3410, 1660, 1620, and 1580 cm⁻¹ ; δ_(H) [(CD₃)₂ SO]1.57 (1H, m, 3'-H), 1.77 (2H, m, 2'-H), 3.37 (2H, d, J 4.4 Hz, CH₂ OH),3.77 (2H, t, J 5.6 Hz, CH₂ OP), 4.12 (2H, t, J 7.4 Hz, 1'-H), 6.48 (2H,s, D₂ O exchangeable, 2-NH₂), 8.08 (1H, s, 8-H), and 8.54 (1H, s, 6-H);(Found: C, 35.53; H, 5.93; N, 22.24%. C₁₀ H₁₆ N₅ O₅ P.0.5NH₃.H₂ Orequires C, 34.94; H, 5.72; N, 22.41%).

EXAMPLE 13 2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine4':4"-phosphate

To an ice-cooled solution of phosphorus oxychloride (93 μl, 1.0 mmol) inpyridine (2 ml) was added dropwise over 45 minutes a solution of9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine(0.46 g, 0.9 mmol) in pyridine (4 ml). The solution was stirred for afurther 20 minutes at room temperature and was then added dropwise to asolution of sodium bicarbonate (0.34 g, 4.0 mmol) in water (6 ml). Thesolvent was removed and the residue was taken up in 80% acetic acid (9ml) and the solution was stirred at 70° for 25 minutes. The solvent wasremoved and the residue was taken up in water and brought to pH 6 byaddition of ammonia. The solution was extracted twice with chloroformand the solvent was removed. The residue was purified by preparativehigh pressure liquid chromatography on a C₁₈ reverse-phase μ-Bondapackcolumn eluting with 4% methanol in ammonium acetate buffer (pH 4.5, 50mM) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine4':4"-phosphate as a white powder (225 mg, 75%); λ_(max) (H₂ O) 220,242, and 303 nm; ν_(max) (KBr) 2900-3200 (br), 1705, 1615, and 1580 cm⁻¹; δ_(H) [(CD₃)₂ SO] 1.63 (1H, m, 3'-H), 1.74 (2H, q, J 7.0 Hz, 2'-H),3.80 (2H, q, J 9.2 Hz, 2×H_(ax)), 3.98 (2H, ddd, J 14.3, 10.9, and 3.5Hz, 2×H_(eq)), 4.08 (2H, t, J 7.1 Hz, 1'-H), 6.51 (2H, s, D₂ Oexchangeable, 2-NH₂), 8.10 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found:C, 36.41; H, 5.18; N, 22.38%. C₁₀ H₁₄ N₅ O₄ P.0.3 NH₃. 1.5H₂ O requiresC, 36.25; H, 5.45; N, 22.40%).

BIOLOGICAL DATA Xanthine Oxidase Catalysed Oxidation of2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine

To an aqueous solution of2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (0.5 mM, 0.7 ml;pH7) was added bovine milk xanthine oxidase (20 μl, 0.4 unit). Dissolvedatmosphere oxygen was allowed to act as electron acceptor and changes inthe UV spectrum were measured. After 4 minutes 25% conversion hadoccurred and after 2.5 hours conversion was essentially complete. Theoxidation product was identified as9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine by its UV spectrum and HPLCretention time.

(Incubation of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine withxanthine oxidase under identical conditions resulted in no change over a2 hour period.)

Oral Absorption of 2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purineand 2-Amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine and theirConversion to 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine in MiceProcedure

2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine,2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine and9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine were administered by oralgavage (0.2 mmoles/kg in 0.1 ml of 1% carboxymethyl cellulose) to 20 gfemale Balb/C mice which had been starved for 18 hours. Fifteen, 60 and180 minutes later, blood was collected from three mice per time point bycardiac puncture using heparinised syringes. Equal aliquots at each timewere pooled and an equal volume of 16% trichloroacetic acid added.Following centrifugation (8,500 g) to remove precipitated proteins, 0.5ml of supernatant was immediately added to 0.1 ml of saturated sodiumbicarbonate solution and the resulting mixture analysed by highperformance liquid chromatography or stored at -20° C. prior toanalysis.

Results

    __________________________________________________________________________                           Concentration of 9-(4-hydroxy-3-hydroxy-                                      methylbut-1-yl)guanine (μg/ml) in blood                                    at stated times after administration                   Administered Compound  15 min  1 hr  3 hr                                     __________________________________________________________________________          9-(4-Hydroxy-3-hydroxy-                                                                        0.7     0.4   0.1                                            methylbut-1-yl(guanine                                                  Expt. 1                                                                             2-Amino-9-(4-hydroxy-                                                                          3.0     2.2   0.3                                            3-hydroxymethylbut-1-                                                         yl)purine                                                                     9-(4-Hydroxy-3-hydroxy-                                                                        1.3     1.0   0.4                                            methylbut-1-yl)guanine                                                        2-Amino-9-(4-hydroxy-                                                                          4.6     2.8   0.6                                            3-hydroxymethylbut-1-                                                   Expt. 2                                                                             yl)purine                                                                     2-Amino-9-(4-acetoxy-                                                                          18.7    4.3   0.3                                            3-acetoxymethylbut-1-                                                         yl)purine                                                                     9-(4-Hydroxy-3-hydroxy-                                                                        1.4     1.1   0.5                                            methylbut-1-yl)guanine                                                        2-Amino-9-(4-hydroxy-3-                                                                        4.8     4.6   1.2                                            hydroxymethylbut-1-yl)                                                        purine                                                                        9-(4-acetoxy-3-  12.9    5.1   0.3                                            hydroxymethylbut-1-yl)-                                                 Expt. 3                                                                             2-aminopurine                                                                 2-Amino-9-(3-hydroxy-                                                                          13.7    5.6   0.7                                            methyl-4-methoxycarbonyloxybut-                                               1-yl)purine                                                                   2-Amino-9-[2-(2,2-                                                                             8.4     2.8   0.8                                            dimethyl-1,3-dioxan-5-                                                        yl)ethyl]purine                                                               9-(4-Hydroxy-3-hydroxy-                                                                        1.1     0.9   0.4                                            methylbut-1-yl)quanine                                                        2-Amino-9-(4-hydroxy-3-                                                                        3.5     4.0   0.8                                            hydroxymethylbut-1-yl)                                                        purine                                                                        2-Amino-9-(4-propionyloxy-                                                                     20.0    6.6   0.5                                            3-propionyloxymethylbut-1-                                              Expt. 4                                                                             yl)purine                                                                     2-Amino-9-(4-butyryloxy-3-                                                                     16.2    7.1   0.5                                            hydroxymethylbut-1-yl)                                                        purine                                                                        2-Amino-9-(4-benzoyloxy-3-                                                                     16.0    6.6   0.3                                            hydroxymethylbut-1-yl)                                                        purine                                                                        9-(4-hydroxy-3-hydroxymethylbut-                                                               1.3     1.0   0.2                                            1-yl)guanine                                                                  2-amino-9-(4-hydroxy-3-hydroxy-                                                                4.1     4.1   1.4                                            methylbut-1-yl)purine                                                   Expt. 5                                                                             2-amino-9-(4-hydroxy-3-hydroxy-                                                                2.2     4.3   1.3                                            methylbut-1-yl)purine 4'-phosphate                                            2-amino-9-(4-hydroxy-3-hydroxy-                                                                0.2     0.2   0.7                                            methylbut-1-yl)purine 4': 4"-                                                 phosphate                                                               __________________________________________________________________________

We claim:
 1. A compound of Formula (I) ##STR19## or a pharmaceuticallyacceptable salt thereof, where R₁ and R₂ are each independentlyhydrogen, or a carboxylic acyl provided that R₁ and R₂ are not bothhydrogen; or R₁ and R₂ are joined together to form a cyclic acetal groupor a cyclic carbonate group.
 2. A compound according to claim 1 whereinR₁ and/or R₂ is a carboxylic acyl group such that the group R₁ O--and/or R₂ O-- is a pharmaceutically acceptable ester group.
 3. Acompound according to claim 2 wherein the carboxylic acyl group R₁and/or R₂ is a group ##STR20## wherein R₃ is C₁₋₆ alkyl, C₁₋₆ alkoxy oraryloptionally substituted with one or two groups selected from C₁₋₆alkyl, C₁₋₆ alkoxy and halo.
 4. A compound according to claim 1 whereinR₁ and R₂ are joined together to form a group ##STR21## or ##STR22## 5.A compound according to claim 4 wherein R₁ and R₂ are joined together asa C(CH₃)₂ group.
 6. A compound according to claim 1 selectedfrom2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine;2-amino-9-(4-acetoxy-3-hydroxymethylbut-1-yl)purine;2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine;2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine;2-amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine;2-amino-9-(4-butyryloxyl-3-hydroxymethylbut-1-yl)purine;2-amino-9-(4-benzoyloxyl-3-hydroxymethylbut-1-yl)purine;andpharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition for treating viral infections which comprises a compound offormula (I) as defined in claim 1 in combination with a pharmaceuticallyacceptable carrier.
 8. A method of treating viral infections in a humanor non-human animal, which comprises administering to the animal aneffective, non-toxic amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.
 9. A compound named2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine
 10. A method oftreating herpesvirus infection in a human or non-human animal, whichcomprises administering to the animal an effective, non-toxic amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.11. A method of claim 10 wherein the herpesvirus is herpes simplex type1 (HSV-1).
 12. A method of claim 10 wherein the herpesvirus is herpessimplex type 2 (HSV-2).
 13. A method of claim 10 wherein the herpesvirusis varicella zoster.
 14. A method of claim 8 wherein the compound is2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine.
 15. A method ofclaim 10 wherein the compound is2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine or apharmaceutically acceptable salt thereof.
 16. A method of claim 15wherein the herpesvirus is herpes simplex type 1 (HSV-1).
 17. A methodof claim 15 wherein the herpesvirus is herpes simplex type 2 (HSV-2).18. A method of claim 15 wherein the herpesvirus is varicella zoster.19. A pharmaceutical composition of claim 7 wherein the compound is2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine.